Anatomical And Behavioral Investigation Of C1ql3 In The Mouse Suprachiasmatic Nucleus, David C. Martinelli

UCHC Articles - Research

Many biochemical, physiological, and behavioral processes such as glucose metabolism, body temperature, and sleep-wake cycles show regular daily rhythms. These circadian rhythms are adjusted to the environmental light-dark cycle by a central pacemaker located in the suprachiasmatic nucleus (SCN) in order for the processes to occur at appropriate times of day. Here, we investigated the expression and function of a synaptic organizing protein, C1QL3, in the SCN. We found that C1ql3 is robustly expressed in the SCN. C1ql3 knockout mice have a reduced density of excitatory synapses in the SCN. In addition, these mice exhibited less consolidated activity to the …

Psma Redirects Cell Survival Signaling From The Mapk To The Pi3k-Akt Pathways To Promote The Progression Of Prostate Cancer, Leslie Ann Caromile, Kristina Dortche, M. Mamunur Rahman, Christina L. Grant, Christopher Stoddard, Linda H. Shapiro

UCHC Articles - Research

Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA …

Extended Therapeutic Window Of A Novel Peptide Inhibitor Of Trpm2 Channels Following Focal Cerebral Ischemia, Venugopal Reddy Venna

UCHC Articles - Research

Abstract

Introduction

TRPM2 channels have been suggested to play a role in ischemic neuronal injury, specifically in males. A major hindrance to TRPM2 research has been the lack of specific TRPM2 inhibitors. The current study characterized the specificity and neuroprotective efficacy of a novel TRPM2 inhibitor.

Methods

Fluorescent calcium imaging (Fluo5F) was used to determine inhibitor efficacy of the TRPM2 peptide inhibitor (tat-M2NX) in HEK293 cells stably expressing hTRPM2. Adult (2–3months) and aged (18–20 months) mice were subjected to 60 min middle cerebral artery occlusion (MCAO) and injected with tat-M2NX, control scrambled peptide (tat-SCR) or clotrimazole (CTZ) either 20 min …

Tnf And Cd28 Signaling Play Unique But Complementary Roles In The Systemic Recruitment Of Innate Immune Cells After Staphylococcus Aureus Enterotoxin A Inhalation, Julia Svedova, Naomi Tsurutani, Wenhai Liu, Kamal M. Khanna, Anthony T. Vella

UCHC Articles - Research

TNF and CD28 Signaling Play Unique but Complementary Roles in the Systemic Recruitment of Innate Immune Cells after Staphylococcus aureus Enterotoxin A Inhalation.

Ischemic Stroke Induces Gut Permeability And Enhances Bacterial Translocation Leading To Sepsis In Aged Mice, Venugopal Reddy Venna, Joshua Crapser, Rodney Ritzel, Rajkumar Verma, Fudong Liu, Anjali Chauhan, Edward Koellhoffer, Austin Ricker, Kendra Maas, Joerg Graf, Louise D. Mccullough

UCHC Articles - Research

Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of …

Cyclin-Dependent Kinase Crk9, Required For Spliced Leader Trans Splicing Of Pre-Mrna In Trypanosomes, Functions In A Complex With A New L-Type Cyclin And A Kinetoplastid-Specific Protein., Nitika Badjatia, Sung Hee Park, Daniela L. Ambrósio, Justin K. Kirkham, Arthur Günzl

UCHC Articles - Research

In eukaryotes, cyclin-dependent kinases (CDKs) control the cell cycle and critical steps in gene expression. The lethal parasite Trypanosoma brucei, member of the phylogenetic order Kinetoplastida, possesses eleven CDKs which, due to high sequence divergence, were generically termed CDC2-related kinases (CRKs). While several CRKs have been implied in the cell cycle, CRK9 was the first trypanosome CDK shown to control the unusual mode of gene expression found in kinetoplastids. In these organisms, protein-coding genes are arranged in tandem arrays which are transcribed polycistronically. Individual mRNAs are processed from precursor RNA by spliced leader (SL) trans splicing and polyadenylation. CRK9 …

Dnah6 And Its Interactions With Pcd Genes In Heterotaxy And Primary Ciliary Dyskinesia, Stephen M. King

UCHC Articles - Research

Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), a sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology involving mutations in cilia genes, a reflection of the common requirement for motile cilia in left-right patterning and airway clearance. While PCD is a monogenic recessive disorder, heterotaxy has a more complex, largely non-monogenic etiology. In this study, we show mutations in the novel dynein gene DNAH6 can cause heterotaxy and ciliary dysfunction similar to PCD. We provide the first evidence that trans-heterozygous interactions between DNAH6 and …

Does A Positive Margin Always Mandate Adjuvant Radiotherapy?, Peter C. Albertsen

UCHC Articles - Research

The appropriate treatment for clinically localized prostate cancer continues to generate controversy. For men with low grade disease it is unclear whether surgery or radiati on therapy provides a survival advantage over active surveillance, and among men with high grade disease it is unclear how many derive a substantial benefit from either intervention. No trial has yet to compare surgery and radiation with observation, but the recent update of the Scandinavian Prostate Cancer Group 4 study suggests that radical prostatectomy provides a significant survival advantage for younger men with intermediate grade diseas

From Conceptual Pluralism To Practical Agreement On Policy: Global Responsibility For Global Health, Audrey Chapman

UCHC Articles - Research

Background

As the human cost of the global economic crisis becomes apparent the ongoing discussions surrounding the post-2015 global development framework continue at a frenzied pace. Given the scale and scope of increased globalization moving forward in a post-Millennium Development Goals era, to protect and realize health equity for all people, has never been more challenging or more important. The unprecedented nature of global interdependence underscores the importance of proposing policy solutions that advance realizing global responsibility for global health.

Discussion

This article argues for advancing global responsibility for global health through the creation of a Global Fund for Health. …

Optimizing Production Of Fc-Amidated Peptides By Chinese Hamster Ovary Cells, Kristina Carlson, Richard E. Mains, Betty A. Eipper

UCHC Articles - Research

Background

Amidation of the carboxyl terminal of many peptides is essential for full biological potency, often increasing receptor binding and stability. The single enzyme responsible for this reaction is peptidylglycine α-amidating monooxygenase (PAM: EC 1.14.17.3), a copper- and ascorbate-dependent Type I membrane protein.

Methods

To make large amounts of high molecular weight amidated product, Chinese hamster ovary (CHO) cells were engineered to express exogenous PAM. To vary access of the enzyme to its substrate, exogenous PAM was targeted to the endoplasmic reticulum, trans-Golgi network, endosomes and lysosomes or to the lumen of the secretory pathway.

Results

PAM was equally …

Sex Differences And The Role Of Il-10 In Ischemic Stroke Recovery., Sarah E. Conway, Meaghan Roy O’Reilly, Brett Friedler, Ilene Staff, Gilbert Fortunato, Louise D. Mccullough

UCHC Articles - Research

Females experience poorer recovery after ischemic stroke compared to males, even after controlling for age and stroke severity. IL-10 is an anti-inflammatory cytokine produced by T regulatory cells and Th2 CD4⁺ helper T cells. In ischemic stroke, an excessive IL-10 response contributes to post-stroke immunosuppression, which worsens outcomes. However, it is unknown if sex differences exist in IL-10 levels after ischemic stroke. In this study, we found that higher levels of IL-10 were associated with poor acute and long-term outcomes after ischemic stroke in female patients but not in males. After controlling for confounders, IL-10 was not an independent …

Correlating Optical Coherence Elastography Based Strain Measurements With Collagen Content Of The Human Ovarian Tissue, Sreyankar Nandy, Hassan S. Salehi, Tianheng Wang, Xiaohong Wang, Melinda Sanders, Angela Kueck, Molly A. Brewer, Quing Zhu

UCHC Articles - Research

In this manuscript, the initial feasibility of a catheter based phase stabilized swept source optical coherence tomography (OCT) system was studied for characterization of the strain inside different human ovarian tissue groups. The ovarian tissue samples were periodically compressed with 500 Hz square wave signal along the axial direction between the surface of an unfocused transducer and a glass cover slide. The displacement and corresponding strain were calculated during loading from different locations for each tissue sample. A total of 27 ex vivo ovaries from 16 patients were investigated. Statistically significant difference (p < 0.001) was observed between the average displacement and strain of the normal and malignant tissue groups. A sensitivity of 93.2% and a specificity of 83% were achieved using 25 microstrain (με) as the threshold. The collagen content of the tissues was quantified from the Sirius Red stained histological sections. The average collagen area fraction (CAF) obtained from the tissue groups were found to have a strong negative correlation (R = -0.75, p < 0.0001) with the amount of strain inside the tissue. This indicates much softer and degenerated tissue structure for the malignant ovaries as compared to the dense, collagen rich structure of the normal ovarian tissue. The initial results indicate that the swept source OCT system can be useful for estimating the elasticity of the human ovarian tissue.

Willpower Versus “Skillpower:” Examining How Self-Efficacy Works In Treatment For Marijuana Dependence, Ronald M. Kadden, Mark D. Litt

UCHC Articles - Research

Self-efficacy has repeatedly been demonstrated to be a robust predictor of outcomes in the treatment of marijuana use disorders. It is not clear, however, how increases in confidence in ability to refrain from use get translated into actual improvements in drug-related outcomes. Marlatt, among others, viewed the acquisition and use of coping skills as the key to behavior change, and self-efficacy as a cognitive state that enabled coping. But that model of behavior change has not been supported, and few studies have shown that the effects of self-efficacy are mediated by coping or by other processes. The current study combined …

A Review Of Graphical Approaches To Common Statistical Analyses : The Omnipresence Of Latent Variables In Statistics, Emil N. Coman, Judith Fifield, Maria A. Coman

UCHC Articles - Research

We provide a comprehensive review of simple and advanced statistical analyses using an intuitive visual approach explicitly modeling Latent Variables (LV). This method can better illuminate what is assumed in each analytical method and what is actually estimated, by translating the causal relationships embedded in the graphical models in equation form. We recommend the graphical display rooted in the century old path analysis, that details all parameters of each statistical model, and suggest labeling that clarifies what is given vs. what is estimated. We link in the process classical and modern analyses under the encompassing broader umbrella of Generalized Latent …

Phosphorylation State-Dependent Interaction Between Akap7Δ/Γ And Phospholamban Increases Phospholamban Phosphorylation., Marc Rigatti, Andrew V. Le, Claire Gerber, Ion I. Moraru, Kimberly L. Dodge-Kafka

UCHC Articles - Research

Changes in heart rate and contractility in response to sympathetic stimulation occur via activation of cAMP dependent protein kinase A (PKA), leading to phosphorylation of numerous substrates that alter Ca²⁺ cycling. Phosphorylation of these substrates is coordinated by A-kinase anchoring proteins (AKAPs), which recruit PKA to specific substrates [1]. Phosphorylation of the PKA substrate phospholamban (PLB) is a critical determinant of Ca²⁺ re-entry into the sarcoplasmic reticulum and is coordinated by AKAP7δ/γ [2,3]. Here, we further these findings by showing that phosphorylation of PLB requires interaction with AKAP7δ/γ and that this interaction …

Long-Term Effects Of Childhood Risk Factors On Cardiovascular Health During Adulthood, Roman Shrestha, Michael Copenhaver

UCHC Articles - Research

The primary purpose of this article is to provide a broad overview of the research on the long-term effects of childhood risk factors on cardiovascular diseases (CVDs) during adulthood and to outline recommendations for prevention of CVDs based on evidence-based interventions (EBIs). CVDs are the leading cause of death and a major cause of disability in the United States and globally. Risk factors for CVDs are already identifiable in children and youth, and include both modifiable factors (e.g., unhealthy diet, physical inactivity, tobacco smoking), and factors that cannot be changed (e.g., age, heredity, sex). A fundamental issue has been the …

Cloning And Variation Of Ground State Intestinal Stem Cells, Lane H. Wilson, Francisco A. Sylvester, Jeffrey S. Hyams, Thomas Devers, Wa Xian

UCHC Articles - Research

Stem cells of the gastrointestinal tract, pancreas, liver, and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, “ground state” stem cells of the human intestine and colon. We show that derived stem cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells likely enforces the functional specificity of the adult intestinal tract. Using clonally-derived colonic epithelia, we show …

Association Of The Lipoprotein Receptor Scarb1 Common Missense Variant Rs4238001 With Incident Coronary Heart Disease, Annabelle Rodriguez-Oquendo

UCHC Articles - Research

Background

Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).

Methods and Results

Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, …

Rlt-S: A Web System For Record Linkage, Robert H. Aseltine, Sanguthevar Rajasekaran, Abdullah-Al Mamun

UCHC Articles - Research

Abstract

Background

Record linkage integrates records across multiple related data sources identifying duplicates and accounting for possible errors. Real life applications require efficient algorithms to merge these voluminous data sources to find out all records belonging to same individuals. Our recently devised highly efficient record linkage algorithms provide best-known solutions to this challenging problem.

Method

We have developed RLT-S, a freely available web tool, which implements our single linkage clustering algorithm for record linkage. This tool requires input data sets and a small set of configuration settings about these files to work efficiently. RLT-S employs exact match clustering, blocking on …

Proteo-Lipobeads For The Oriented Encapsulation Of Membrane Proteins, Leslie M. Loew

UCHC Articles - Research

As a surrogate of the life cell, proteo-lipobeads are presented, encapsulating functional membrane proteins in a strict orientation into a lipid bilayer. Assays can be performed just as on life cells, for example using fluorescence measurements. As a proof of concept, we have demonstrated proton transport through cytochrome c oxidase.

Role For Endogenous Bdnf In Endocannabinoid-Mediated Long-Term Depression At Neocortical Inhibitory Synapses, Eric S. Levine, Liangfang Zhao, Mason Li-Wen Yeh

UCHC Articles - Research

The endogenous cannabinoid (endocannabinoid) system is an important regulator of synaptic function. Endocannabinoids acutely modulate inhibitory and excitatory transmission, and also mediate long-term depression at GABAergic and glutamatergic synapses. Typically, endocannabinoid synthesis and release is stimulated by depolarization-induced calcium influx and/or activation of phospholipase-C (PLC) signaling triggered by mGluR activation. Recently it has been shown that brain-derived neurotrophic factor (BDNF) can also induce endocannabinoid release. Although there is growing evidence for cross-talk between BDNF and endocannabinoid signaling, little is known about the functional relevance of these interactions. In the present studies, we examined BDNF – endocannabinoid interactions in regulating activity-dependent …

Vasculogenesis And Angiogenesis In Vegf Receptor-1 Deficient Mice, Vivienne C. Ho, Guo-Hua Fong

UCHC Articles - Research

Vascular endothelial growth factor receptor-1 (VEGFR-1)/Flt-1 is a transmembrane tyrosine kinase receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF). VEGFR-1 is an enigmatic molecule whose precise role in postnatal angiogenesis remains controversial. Although many postnatal and adult studies have been performed by manipulating VEGFR-1 ligands, including competitive binding by truncated VEGFR-1 protein, neutralization by antibodies, or specific ligand overexpression or knockout, much less is known at the level of the receptor per se, especially in vivo. Perplexingly, while VEGFR-1 negatively regulates endothelial cell differentiation during development, it has been implied in promoting angiogenesis under certain conditions in adult tissues, …

Why Is Co-Infection With Influenza Virus And Bacteria So Difficult To Control?, Linda S. Cauley, Anthony T. Vella

UCHC Articles - Research

Influenza viruses are genetically labile pathogens which avoid immune detection by constantly changing their coat proteins. Most human infections are caused by mildly pathogenic viruses which rarely cause life-threatening disease in healthy people, but some individuals with a weakened immune system can experience severe complications. Widespread infections with highly pathogenic strains of influenza virus are less common, but have the potential to cause enormous death tolls among healthy adults if infection rates reach pandemic proportions. Increased virulence has been attributed to a variety of factors, including enhanced susceptibility to co-infection with common strains of bacteria. The mechanisms that facilitate dual …

Interpersonal Guilt And Substance Use In College Students, Nancy M. Petry

UCHC Articles - Research

The college years are a time for developing independence and separating from one’s family, and it is also a time in which substance use often escalates. This study examined the relationships between use of substances and interpersonal guilt, an emotion that can arise from feelings about separation, among 1,979 college students. Regular users of alcohol, cigarettes, cannabis, and other illicit drugs were compared with non-regular users of each substance. Sequential linear regression, controlling for confounding variables, examined relationships between regular use of each substance and scores on a guilt index. Risky drinkers and daily smokers had significantly more interpersonal guilt …

Imaging Submillisecond Membrane Potential Changes From Individual Regions Of Single Axons, Dendrites And Spines, Srdjan D. Antic

UCHC Articles - Research

A central question in neuronal network analysis is how the interaction between individual neurons produces behavior and behavioral modifications. This task depends critically on how exactly signals are integrated by individual nerve cells functioning as complex operational units. Regional electrical properties of branching neuronal processes which determine the input-output function of any neuron are extraordinarily complex, dynamic, and, in the general case, impossible to predict in the absence of detailed measurements. To obtain such a measurement one would, ideally, like to be able to monitor, at multiple sites, subthreshold events as they travel from the sites of origin (synaptic contacts …

Genome-Wide Analysis Of Drosophila Circular Rnas Reveals Their Structural And Sequence Properties And Age-Dependent Neural Accumulation, Sarah Olson, Brenton R. Graveley

UCHC Articles - Research

Circularization was recently recognized to broadly expand transcriptome complexity. Here, we exploit massive Drosophila total RNA-sequencing data, >5 billion paired-end reads from >100 libraries covering diverse developmental stages, tissues, and cultured cells, to rigorously annotate >2,500 fruit fly circular RNAs. These mostly derive from back-splicing of protein-coding genes and lack poly(A) tails, and the circularization of hundreds of genes is conserved across multiple Drosophila species. We elucidate structural and sequence properties of Drosophila circular RNAs, which exhibit commonalities and distinctions from mammalian circles. Notably, Drosophila circular RNAs harbor >1,000 well-conserved canonical miRNA seed matches, especially within coding regions, and coding …

Therapeutic Targeting Of The Inflammome, Kyle T. Wright, Charles Giardina, Anthony T. Vella

UCHC Articles - Research

Inflammatory responses can vary depending on a myriad of factors including: 1) the initiating stimulus or trigger, 2) the cell types, involved in the response, and 3) the specific effector cytokine-chemokine milieus produced. The compilation of these and other factors in a given mechanistic context is sometimes referred to as the “inflammome”. Humans and other higher order mammals have evolved (over time) several discrete inflammomes to counter the effects of pathogens. However, when these inflammomes are induced inappropriately, they drive the development of chronic inflammatory diseases. The vast majority of biological anti-inflammatory treatments currently being developed are focused on the …

Pathophysiology And Animal Modeling Of Underactive Bladder, Phillip P. Smith, George A. Kuchel

UCHC Articles - Research

While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.

Biphasic Effects Of Fgf2 On Odontoblast Differentiation Involve Changes In The Bmp And Wnt Signaling Pathways, Karen Sagomonyants, Mina Mina

UCHC Articles - Research

Odontoblast differentiation during physiological and reparative dentinogenesis is dependent upon multiple signaling molecules, including Fibroblast Growth Factors (FGFs), Bone Morphogenetic Proteins (BMPs) and Wingless/Integrated (Wnt) ligands. Recent studies in our laboratory showed that continuous exposure of primary dental pulp cultures to FGF2 exerted biphasic effects on the expression of markers of dentinogenesis. In the present study we examined the possible involvement of the BMP and Wnt signaling pathways in mediating the effects of FGF2 on dental pulp cells. Our results showed that stimulatory effects of FGF2 on dentinogenesis during the proliferation phase of growth were associated with increased expression of …

Non-Surgical And Supportive Periodontal Therapy: Predictors Of Compliance, Efthimia Effie Ioannidou

UCHC Articles - Research

Aim

To identify predictors of compliance during non-surgical and supportive periodontal therapy (SPT).

Materials and Methods

In this retrospective study, demographic, dental, medical data of 427 new patients in a private practice were collected. Data were analysed in statistical models with non-surgical therapy and SPT compliance used as dependent variables.

Results

Of the 427 patients, 17.3% never agreed to initial therapy, 10.7% never completed therapy and 20.8% completed treatment, but never entered SPT. Of the 218 SPT patients, 56% became non-attenders after a period of 20 months, 33% were erratic attenders and 10.5% were regular attenders until the end of …